尿苷肽类化合物因具有特异的抗结核活性和新颖的作用靶点成为寻找新型抗结核药物的先导化合物。但已知尿苷肽类化合物结构类型单一，成药性有待提高，而利用化学合成、突变合成等方法进行结构改造的效果不甚理想，亟需发掘新的生物合成元件以丰富此类化合物的结构多样性。本项目拟以生物合成基因为指导进行定向基因组发掘，通过生物信息学分析从微生物中发现潜在的新型尿苷肽类化合物生物合成基因簇和新的遗传元件，预测并表征生物合成元件的功能从而丰富此类化合物的遗传元件库。在此基础上，以合成生物学为指导，在异源宿主中利用获得的新元件进行替换与组合，对合成的化合物进行分析、分离纯化与结构鉴定，从中发现抗结核活性提高的新化合物。通过本项目的实施将建立天然来源的尿苷肽类化合物遗传元件库，获得结构多样的新化合物，为新型抗多重耐药结核分枝杆菌药物研发提供物质基础，同时有利于推进合成生物学技术在天然产物结构改造中的应用。

Uridyl peptide compounds have become lead compounds for discovering new anti-tuberculosis drugs due to their unique chemical structure, good antibacterial activity and the novel target. But its development has been hampered by their poor structural diversity and pharmaceutical properties. Besides, structural modifications with current methods such as semi-synthesis, precursor-directed biosynthesis and mutational biosynthesis have a little effect on improving their properties. So there is an urgent need to discover new biosynthetic elements to enrich uridyl peptide compounds for the improvement of its druggability. In this research, the biosynthetic gene directed genome mining was employed to explore new uridyl peptide gene clusters and novel genetic elements from microbes by bioinformatics analysis. Then functional prediction and characterization of the potential biosynthetic elements were made to get a rich genetic element library of uridyl peptide compounds. Based on this library, synthetic biological technologies will be employed to obtain novel uridyl peptide compounds by substitution and combination of genetic elements in heterologous host. The newly produced compounds will be detected, purified and structurally identified by a series of chemical methods. Finally, new uridyl peptide compounds with improved anti-tuberculosis activity will be gained through screening. The implementation of this project will build a natural genetic element library of uridyl peptide compounds and produce a large number of novel uridyl peptide compounds with diverse structures, which will not only set foundation for discovering better lead compound combating multi-drug resistant Mycobacterium tuberculosis infection, but also promote the application of synthetic biological technology in structural modification of natural products.